Ubiquitin as a degradation signal.

Johnson, Erica S.; Bartel, Bonnie; Seufert, Wolfgang; Varshavsky, Alexander

doi:10.1002/j.1460-2075.1992.tb05080.x

Cited by 247 publications

(215 citation statements)

References 38 publications

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“…1B) and the failure of Ub ϩ1 to bind E1 (Fig. 1C) are in agreement with earlier demonstrations that G76 is a key specificity element in Ub processing and activation (4,(26)(27)(28)(29)(30). It is therefore most unlikely that Ub ϩ1 will inhibit the conjugation of wild-type Ub to cellular substrates.…”

Section: Resultssupporting

confidence: 91%

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Lam

Pickart

Alban

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

307

211

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Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub ؉1 , has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub ؉1 expression should be deleterious. Here we show that Ub ؉1 is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub ؉1 in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.

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Section: Resultssupporting

confidence: 91%

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Lam

Pickart

Alban

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

307

211

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“…The substrates of another Ub-dependent proteolytic system, termed the UFD pathway, include proteins bearing at their N termini a ''nonremovable'' Ub moiety (23,37,38). A partial or complete resistance of these Ub-containing proteins to deubiquitylating enzyme-mediated cleavage stems from either alterations of the last residue of Ub moiety or the presence of proline at the C-terminal side of the Ub-protein junction (23).…”

Section: Coli-expressedmentioning

confidence: 99%

Physical association of ubiquitin ligases and the 26S proteasome

Xie

Varshavsky

2000

Proc. Natl. Acad. Sci. U.S.A.

170

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The ubiquitin (Ub) system recognizes degradation signals of the target proteins through the E3 components of E3-E2 Ub ligases. A targeted substrate bears a covalently linked multi-Ub chain and is degraded by the ATP-dependent 26S proteasome, which consists of the 20S core protease and two 19S particles. The latter mediate the binding and unfolding of a substrate protein before its transfer to the interior of the 20S core. It is unclear how a targeted substrate is delivered to the 26S proteasome, inasmuch as Rpn10p, the only known proteasomal subunit that binds multi-Ub chains, has been found to be not essential for degradation of many proteins in the yeast Saccharomyces cerevisiae. Here we show that Ubr1p and Ufd4p, the E3 components of two distinct Ub ligases, directly interact with the 26S proteasome. Specifically, Ubr1p is shown to bind to the Rpn2p, Rpt1p, and Rpt6p proteins of the 19S particle, and Ufd4p is shown to bind to Rpt6p. These and related results suggest that a substrate-bound Ub ligase participates in the delivery of substrates to the proteasome, because of affinity between the ligase's E3 component and specific proteins of the 19S particle.R egulated proteolysis by the ubiquitin (Ub) system plays essential roles in the cell cycle, differentiation, stress responses, and many other processes (1-5). Ub is a 76-residue protein whose covalent conjugation to other proteins, usually in the form of a multi-Ub chain, marks these proteins for processive degradation by the 26S proteasome, an ATP-dependent multisubunit protease (3, 6-8). The conjugation of Ub to other proteins involves the formation of a thioester between the C terminus of Ub and a specific cysteine of the Ub-activating (E1) enzyme. The Ub moiety of E1ϳUb thioester thereafter is transesterified to a specific cysteine in one of several Ubconjugating (E2) enzymes. The Ub moiety of E2ϳUb thioester is conjugated, via the isopeptide bond, to the -amino group of either a substrate's Lys residue or a Lys residue of another Ub moiety, the latter reaction resulting in a substrate-linked multi-Ub chain (9-11).Most E2 enzymes function in complexes with proteins called E3. The functions of E3s include the initial recognition of degradation signals (degrons) in the substrate proteins, with different E3s recognizing different classes of degrons. The E2-E3 complexes, referred to as Ub ligases, mediate the formation of substrate-linked multi-Ub chains (10, 12, 13). The ATP-dependent 26S proteasome, which processively degrades a targeted, ubiquitylated † substrate, consists of the 20S core protease and two 19S particles (6, 14). A 19S particle mediates the binding and unfolding of a substrate protein before its transfer to the interior of the 20S core (6,(15)(16)(17)(18)(19). It is unclear how a targeted substrate is delivered to the 26S proteasome, inasmuch as Rpn10p (Mcb1p͞Sun1p), the only known proteasomal subunit that binds multi-Ub chains (20), is not essential for degradation of many proteins in the yeast Saccharomyces cerevisiae (21).Here we show tha...

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“…The Ubiquitin Fusion Degradation Pathway Is Not Involved in the Degradation of FBPase-Proteolysis of the N-end rule substrate ubiquitin-Pro-␤-galactosidase via the ubiquitin-mediated pathway requires formation of a multiubiquitin chain by the ubiquitin fusion degradation pathway (UFD) (43). This pathway links the multiubiquitin chain to the amino-terminal proline of the substrates.…”

Section: Table II Stabilization Of N-end Rule Substrates In Gid Mutanmentioning

confidence: 99%

“…The ubiquitin-conjugating enzymes Ubc4 and Ubc5 are necessary for the ubiquitination of FBPase and the N-end rule substrate ubiquitin-Pro-␤-galactosidase (2,43). We examined the involvement of ufd mutants, which are responsible for the degradation of ubiquitin-pro-␤-galactosidase fusion protein, in catabolite degradation of FBPase but found no effect.…”

Section: Fig 6 Ufd4 Is Not Involved In the Degradation Of Fbpasementioning

confidence: 99%

Proteins of Newly Isolated Mutants and the Amino-terminal Proline Are Essential for Ubiquitin-Proteasome-catalyzed Catabolite Degradation of Fructose-1,6-bisphosphatase of Saccharomyces cerevisiae

Hämmerle¹,

Bauer²,

Rose³

et al. 1998

Journal of Biological Chemistry

101

131

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Addition of glucose to cells of the yeast Saccharomyces cerevisiae growing on a non-fermentable carbon source leads to selective and rapid degradation of fructose-1,6-bisphosphatase. This so called catabolite inactivation of the enzyme is brought about by the ubiquitin-proteasome system. To identify additional components of the catabolite inactivation machinery, we isolated three mutant strains, gid1, gid2, and gid3, defective in glucose-induced degradation of fructose-1,6-bisphosphatase. All mutant strains show in addition a defect in catabolite inactivation of three other gluconeogenic enzymes: cytosolic malate dehydrogenase, isocitrate lyase, and phosphoenolpyruvate carboxykinase. These findings indicate a common mechanism for the inactivation of all four enzymes. The mutants were also impaired in degradation of short-lived N-end rule substrates, which are degraded via the ubiquitin-proteasome system. Sitedirected mutagenesis of the amino-terminal proline residue yielded fructose-1,6-bisphosphatase forms that were no longer degraded via the ubiquitin-proteasome pathway. All amino termini other than proline made fructose-1,6-bisphosphatase inaccessible to degradation. However, the exchange of the amino-terminal proline had no effect on the phosphorylation of the mutated enzyme. Our findings suggest an essential function of the amino-terminal proline residue for the degradation process of fructose-1,6-bisphosphatase. Phosphorylation of the enzyme was not necessary for degradation to occur.

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Ubiquitin as a degradation signal.

Cited by 247 publications

References 38 publications

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Inhibition of the ubiquitin-proteasome system in Alzheimer's disease

Physical association of ubiquitin ligases and the 26S proteasome

Proteins of Newly Isolated Mutants and the Amino-terminal Proline Are Essential for Ubiquitin-Proteasome-catalyzed Catabolite Degradation of Fructose-1,6-bisphosphatase of Saccharomyces cerevisiae

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